RESUMO
BACKGROUND: Serum hepatitis B virus (HBV) RNA is a surrogate biomarker for intrahepatic covalently closed circular DNA (cccDNA) transcriptional activity and persistence. In this retrospective study, we investigated its presence, levels and composition in ab initio Hepatitis B e antigen (HBeAg) negative chronically infected patients and examined possible associations with disease activity and the outcome of nucleos(t)ide analogue (NA) discontinuation. METHODS: We developed a sensitive real time polymerase chain reaction (RT-PCR) for the specific detection of HBV pregenomic RNA (pgRNA) and precore (preC) mRNA and analyzed 220 serum specimens, 160 under NA treatment, from 116 Greek patients initially negative for HBeAg. RESULTS: HBV pgRNA was detected in 31% and preC mRNA in 15% of samples, at lower levels representing a small fraction (3.4%) of total core promoter produced transcripts. In the absence of NAs, pgRNA was detected in 57% of samples with median value of 5.19 (2.61-8.35) log10 cp/mL, at lower levels than HBV DNA and correlated significantly with ALT (r = 0.764) and serum HBV DNA (r = 0.906). A wide range of HBV DNA/pgRNA ratio was observed with significant inter- and intra-patient variation. During NA treatment, pgRNA displayed low detectability (22%) and variable levels, median 3.97 (2.30- 8.13) log10 cp/mL, as well as, a significant inverse correlation with the duration of treatment (r = - 0.346, p < 0.01). In 74 events of NA discontinuation, end-of-treatment pgRNA-positive compared to pgRNA-negative cases, experienced more frequently virological (p = 0.016) and clinical (p = 0.011) relapse. CONCLUSIONS: In genotype D ab initio HBeAg negative patients, serum HBV RNA is primarily composed of pgRNA plus a minor fraction of preC mRNA transcripts. Serum pgRNA is associated with disease activity, suggesting lysis of infected hepatocytes as a possible source of serum HBV RNA in untreated patients and in the early phase of NA treatment. During long term NA treatment, detectable serum pgRNA predicts viral rebound and clinical relapse following treatment discontinuation and may thus serve as a marker for the decision of cessation of therapy.
Assuntos
Vírus da Hepatite B , Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral/genética , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , RNA , Estudos RetrospectivosRESUMO
BACKGROUND & AIMS: We investigated whether HBV genotype influences on-treatment HBsAg kinetics and/or the end-of-treatment HBsAg levels associated with long-term virological response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a±lamivudine in the Phase III trial. METHODS: All patients (n=230) who participated in long-term follow-up were included according to the availability of HBsAg level measurements. Long-term virological response was defined as HBV DNA ≤ 10,000cp/ml (1786IU/ml) at 5 years post-treatment. Genotype-specific end-of-treatment HBsAg levels associated with long-term virological response (identified by ROC analysis) were assessed in 199 patients with HBsAg measurements available at baseline and end-of-treatment. HBsAg kinetics according to genotype and long-term virological response were investigated in the 117 patients with additional samples available at weeks 12, 24, and 72. RESULTS: Baseline HBsAg levels were significantly higher for A than B, C, and D genotypes (p<0.05). On-treatment HBsAg kinetics varied according to HBV genotype. The difference between responders and non-responders was greatest for genotype A from weeks 12-24; for genotypes B and D from baseline to week 12; there was no significant difference over any timeframe for genotype C. High positive predictive values for long-term virological response could be obtained by applying end-of-treatment genotype-specific cut-offs: 75%, 47%, 71%, and 75% for genotypes A (<400IU/ml), B (<50IU/ml), C (<75IU/ml), and D (<1000IU/ml), respectively. CONCLUSIONS: On-treatment HBsAg kinetics vary between HBV genotypes. Genotype-specific monitoring timeframes and end-of-treatment thresholds could ameliorate response-guided treatment of HBeAg-negative chronic hepatitis B.
Assuntos
Antivirais/uso terapêutico , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adolescente , Adulto , Idoso , Feminino , Genótipo , Vírus da Hepatite B/classificação , Hepatite B Crônica/virologia , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêuticoRESUMO
BACKGROUND & AIMS: Little is known about the biochemical and virological effects of stopping long-term nucleos(t)ide analogue therapy for hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB). METHODS: We performed a cohort observational study, following 33 HBeAg-negative patients with CHB, undetectable serum HBV DNA, and normal levels of aminotransferases after long-term (4 or 5 years) treatment with adefovir dipivoxil (ADV). All patients were followed for 5.5 years; follow-up visits included measurements of serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), and HBV DNA monthly for the first 6 months and every 3-6 months thereafter. Various factors were measured at baseline, the end of treatment (EOT), and following treatment to identify those associated with clearance of HBsAg. RESULTS: During the first few months of the postdiscontinuation period, all patients experienced virological and 25 (76%) had biochemical relapse. During the follow-up period, 18 patients (55%) who had discontinued antiviral therapy achieved sustained response (HBV DNA level <2000 IU/L, persistently normal level of ALT). Among these, 13 (72%) cleared HBsAg. Fifteen patients (45%) with virological and/or biochemical relapse were re-treated with oral antiviral agents (11 during the first 18 months and 4 after the third year), without evidence of liver decompensation; only 1 lost HBsAg (6%). Higher pretreatment and EOT levels of ALT, no previous treatment with interferon, and lower level of HBsAg at the EOT were significantly associated with HBsAg clearance based on multivariate analysis. CONCLUSIONS: In HBeAg-negative patients with CHB, it is safe and effective to discontinue ADV therapy after 4 or 5 years; 55% of patients have sustained responses, and 39% of patients lose HBsAg.
Assuntos
Adenina/análogos & derivados , Antivirais/administração & dosagem , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos/administração & dosagem , Adenina/administração & dosagem , Adolescente , Adulto , Idoso , Alanina Transaminase/sangue , Biomarcadores/sangue , Distribuição de Qui-Quadrado , DNA Viral/sangue , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Vírus da Hepatite B/genética , Vírus da Hepatite B/crescimento & desenvolvimento , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/diagnóstico , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Recidiva , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
BACKGROUND & AIMS: Peginterferon plus ribavirin has been the standard of care for chronic hepatitis C for a decade and an essential component of combination regimens for this disease. This large multinational open-label study aimed to better define the incidence of serious adverse events (SAEs) and non-serious adverse events of special interest in patients receiving peginterferon alfa-2a/ribavirin. METHODS: Patients were assigned at the investigator's discretion to 24- or 48-week treatment with peginterferon alfa-2a 180 µg/week and ribavirin 800 mg/day or 1000/1200 mg/day. All AEs, defined as SAEs and non-SAEs of special interest, were recorded during treatment and for 12 weeks thereafter. Non-SAEs of special interest included those leading to dose reduction/discontinuation, neutropenia, thrombocytopenia, anaemia, ALT elevations leading to dose modification and unknown/unexpected AEs. RESULTS: Of 1675 and 7178 patients assigned to 24 and 48 weeks of treatment, respectively, 87.6 and 68.3% completed therapy, whereas 6.4 and 10.3% prematurely stopped peginterferon alfa-2a treatment because of AEs. Among patients assigned to 24 and 48 weeks, 37.4 and 46.9%, respectively, reported any AE (SAE or non-SAE of special interest); 4.2 and 6.6% reported SAEs and 35.2 and 44.0% reported non-SAEs of special interest. Female gender, increasing age and cirrhosis were significantly associated with dose reductions of either drug. Increasing age (and female gender in the case of ribavirin) was significantly associated with treatment discontinuation. CONCLUSION: This study confirmed the safety and tolerability profile of peginterferon alfa-2a/ribavirin and identified patient subgroups at higher risk of dose reductions and discontinuations, thus allowing optimum management of AEs.
Assuntos
Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Adulto , Anemia/induzido quimicamente , Anemia/epidemiologia , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Estudos de Coortes , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Hepatite C Crônica/epidemiologia , Humanos , Incidência , Internacionalidade , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Fatores de Risco , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologia , Resultado do TratamentoRESUMO
Data derived from population, case-control, and cohort studies conducted in several Euro-Mediterranean and African countries disclose impressive similarities in the age and modes of hepatitis B virus (HBV) transmission and in the prevalence, duration, and outcome of the four phases of the natural history of chronic infection. Perinatal HBV infection is rare while the vast majority of chronic infections originate from horizontal HBV transmission to infants and children. HBeAg loss and seroconversion to anti-HBe occur in a few years time, usually during the second decade of life. HBeAg-negative/anti-HBe-positive chronic hepatitis B (CHB), predominates in these countries being 7-9 times more frequent than HBeAg-positive CHB. The predominance of HBeAg-negative CHB is largely linked to the molecular characteristics of HBV genotype D prevailing in European and African countries of the Mediterranean basin and of genotype E and subgenotype A1 that prevail in the other parts of Africa. The molecular characteristics of the African subgenotype A1 differ from those of European subgenotype A2 explaining the fact that patients infected subgenotype A1 demonstrate an earlier loss of HBeAg and seroconversion to anti-HBe during the natural course of HBV infection compared to those infected with subgenotype A2. It is proposed that the molecular characteristics of HBV genotypes and subgenotypes prevailing in Euro-Mediterranean and African countries acting in concert with host and environmental factors largely determine the natural history of chronic HBV infection and its significant differences from countries of HBV genotype C and B and of subgenotype Ae predominance. The knowledge of the natural history of chronic HBV infection in Euro-Mediterranean and African countries combined with wide screening programs for prompt recognition and treatment of chronic HBV infection both in its HBeAg-positive and -negative immune reactive phases can be expected to increase the efficacy of current and future therapeutic strategies.
Assuntos
Hepatite B Crônica/etiologia , África/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Anticorpos Anti-Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/história , Hepatite B Crônica/virologia , História do Século XX , História do Século XXI , Humanos , Masculino , Região do Mediterrâneo/epidemiologiaRESUMO
BACKGROUND & AIMS: The probability of response to peginterferon and ribavirin is associated with numerous host and virological factors. Attainment of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 during treatment with peginterferon and ribavirin, is highly predictive of sustained virological response (SVR). The aim of the present study was to determine the relative importance of the kinetics of antiviral response compared to baseline host and virological factors for predicting SVR. METHODS: A retrospective analysis of 1383 patients, encompassing genotypes 1-4, treated with peginterferon alfa-2a and ribavirin, was performed. Baseline characteristics were compared across HCV genotypes and pretreatment factors associated with RVR were identified. The relative significance of RVR compared to other baseline factors for predicting SVR was analyzed by multiple logistic regression analysis. RESULTS: RVR was achieved by 16% of patients with genotype 1 and 71% and 60% of those with genotype 2 and 3, respectively. Among patients who achieved RVR, the rate of SVR was high across all genotypes and ranged from 88% to 100% (genotypes 1-4). Baseline factors predictive of RVR included genotype, younger age, lower initial viral load, higher ALT ratio, absence of advanced fibrosis, and younger age. Notably, the presence of RVR generated the highest odds ratio (5.47, 95% confidence interval 3.97-7.52) for predicting SVR in multiple logistic regression analysis of these factors. CONCLUSIONS: Attainment of RVR varies by genotype and is associated with several baseline factors. Patients who achieve RVR have the highest rates of SVR, regardless of genotype. These findings have important implications for predicting and managing response-guided combination antiviral therapies.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Adulto , Antivirais/administração & dosagem , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/classificação , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , RNA Viral/sangue , Proteínas Recombinantes , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
HCV has been classified into no fewer than six major genotypes and a series of subtypes. Each HCV genotype is unique with respect to its nucleotide sequence, geographic distribution, and response to therapy. Genotypes 1, 2, and 3 are common throughout North America and Europe. HCV genotype 4 (HCV-4) is common in the Middle East and in Africa, where it is responsible for more than 80% of HCV infections. It has recently spread to several European countries. HCV-4 is considered a major cause of chronic hepatitis, cirrhosis, hepatocellular carcinoma, and liver transplantation in these regions. Although HCV-4 is the cause of approximately 20% of the 170 million cases of chronic hepatitis C in the world, it has not been the subject of widespread research. Therefore, this document, drafted by a panel of international experts, aimed to review current knowledge on the epidemiology, natural history, clinical, histological features, and treatment of HCV-4 infections.
Assuntos
Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/terapia , Hepatite C Crônica/virologia , Antivirais/uso terapêutico , Carcinoma Hepatocelular/etiologia , Ensaios Clínicos como Assunto , Genótipo , Hepatite C Crônica/complicações , Hepatite C Crônica/etiologia , Humanos , Interferon Tipo I/uso terapêutico , Interferons , Interleucinas/genética , Neoplasias Hepáticas/etiologia , Transplante de Fígado , Polimorfismo de Nucleotídeo Único , Guias de Prática Clínica como Assunto , Proteínas Recombinantes , Ribavirina/uso terapêuticoRESUMO
The effect of antiviral treatment on apoptosis in chronic hepatitis B (CHB) has not been clarified. We evaluated the hepatic immunohistochemical expression of the pro-apoptotic bax and the antiapoptotic bcl-xL protein in HBeAg-negative CHB patients before and after treatment. In our study we included 72 paired biopsies from 36 HBeAg-negative CHB patients: 29 treated (interferon-alfa: 17, adefovir: 12) and 7 untreated. Changes in expression of apoptotic proteins (D-bax, D-bcl-xL), necroinflammation and fibrosis (D-grade/D-stage) (Ishak classification) were evaluated. We found that Bax-positive compared to bax-negative biopsies had worse necroinflammation (8.2 vs. 6.7, P = 0.05) and fibrosis score (3.9 vs. 3, P = 0.036). bcl-xL-positive compared to bcl-xL-negative biopsies had lower intralobular inflammation (1.6 vs. 2.2, P = 0.03). Decreased compared to stable/increased D-bax was associated with greater improvement in necroinflammation only in treated patients (D-grade: -4.6 vs. -1.6, P = 0.05) and greater fibrosis improvement in interferon treated patients (D-stage: -0.4 vs. 0.55, P = 0.05). Increased compared to stable/decreased total apoptotic trend [D-apoptosis: (D-bax)-(D-bcl-xL)], was associated with worsening fibrosis, particularly in adefovir treated patients (D-stage: 2.3 vs. 0, P = 0.004). In the 11 patients without significant changes from 1st to 2nd biopsy, increased apoptosis was more frequent in treated than untreated cases (P = 0.046). In multivariate analysis, bax change was independently associated with change of grade (P = 0.038) and antiviral therapy (P = 0.015). In conclusions, in HBeAg-negative CHB, histological improvement after treatment is associated with decreased hepatocyte apoptosis. In patients without substantial histological changes, treatment seems to increase the apoptosis of hepatocytes, thus having a possible protective effect on hepatocarcinogenesis.
Assuntos
Antivirais/administração & dosagem , Apoptose/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Fígado/efeitos dos fármacos , Proteína X Associada a bcl-2/biossíntese , Proteína bcl-X/biossíntese , Adenina/administração & dosagem , Adenina/análogos & derivados , Adulto , Biópsia , Feminino , Fibrose/etiologia , Fibrose/patologia , Antígenos E da Hepatite B/análise , Vírus da Hepatite B/crescimento & desenvolvimento , Hepatite B Crônica/complicações , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Humanos , Imuno-Histoquímica , Inflamação/etiologia , Inflamação/patologia , Interferon-alfa/administração & dosagem , Fígado/patologia , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Organofosfonatos/administração & dosagem , Estudos Retrospectivos , Índice de Gravidade de Doença , Proteína X Associada a bcl-2/análise , Proteína bcl-X/análiseRESUMO
UNLABELLED: The objective of this study is to determine the efficacy and safety of peginterferon alfa-2a (40 KD)/ribavirin in patients with advanced fibrosis. Data from 341 genotype 1/4 patients (99 with bridging fibrosis/cirrhosis) treated for 48 weeks and 1547 genotype 2/3 patients (380 with bridging fibrosis/cirrhosis) treated for 16 or 24 weeks enrolled in three randomized international studies were analyzed. Sustained virological response (SVR) rates decreased progressively from 60% in genotype 1/4 patients without advanced fibrosis to 51% in those with bridging fibrosis and 33% in those with cirrhosis (trend test P = 0.0028); and from 76% to 61% and 57%, respectively, in genotype 2/3 patients treated for 24 weeks (trend test P < 0.0001). Irrespective of genotype, patients without advanced fibrosis were more likely to have an earlier response to treatment that was associated with higher SVR rates and lower relapse rates during untreated follow-up. Among patients with or without a diagnosis of advanced fibrosis, rates of SVR and relapse were similar for patients with similar responses in the first 12 weeks. CONCLUSION: Compared with patients with less severe disease, SVR rates are significantly lower in patients with advanced fibrosis. However, irrespective of genotype and degree of fibrosis, the time to become hepatitis C virus (HCV) RNA undetectable was the strongest predictor of SVR.
Assuntos
Antivirais/administração & dosagem , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Interferon-alfa/administração & dosagem , Cirrose Hepática/etiologia , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Adulto , Antivirais/efeitos adversos , Antivirais/farmacologia , Progressão da Doença , Quimioterapia Combinada , Feminino , Hepacivirus/efeitos dos fármacos , Hepatite C/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Interferon-alfa/farmacologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacologia , Proteínas Recombinantes , Ribavirina/efeitos adversos , Ribavirina/farmacologiaRESUMO
There have been numerous research milestones since the discovery of the hepatitis B virus (HBV) in the 1960s. These mark major advances in the serology and epidemiology of HBV infection, in identifying the wide clinical spectrum of acute and chronic hepatic diseases as well as the extrahepatic conditions induced by this virus, the molecular biology of the virus including its variants and mutants, its molecular diagnosis and monitoring, the host immune responses to the infecting virus, the pathogenesis and immunopathogenesis of liver disease as well as its natural course and outcome. These landmark discoveries are the firm background for current and future developments in treatment. There are three consecutive and partly overlapping chronological periods to treatment milestones beginning with recombinant standard interferon-alpha (IFN-α) in the 1980s, then oral antivirals from 1998 to the present and in 2005 pegylated IFN-α (PEG-IFN). The renewed interest in PEG-IFN-α treatment is now focused on both HBeAg-positive and HBeAg-negative chronic hepatitis B and it now also aims at HBsAg loss when associated with on-treatment monitoring of serum HBV DNA and HBsAg levels, resulting in the closest thing to a cure of hepatitis B. The impressive progress made in all aspects of hepatitis B research suggests that curative therapy may be developed for all patients and for all phases of HBV infection in the foreseeable future. However for the moment, realistic efforts should be made to make treatment as widely available and affordable as possible and to apply current therapies to significantly reduce HBV morbidity and mortality.
Assuntos
Antivirais/uso terapêutico , Hepatite B/tratamento farmacológico , Hepatite B/história , Hepatite B/fisiopatologia , DNA Viral/sangue , Antígenos de Superfície da Hepatite B/sangue , História do Século XX , História do Século XXI , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Proteínas RecombinantesRESUMO
BACKGROUND & AIMS: Assessing hepatitis C virus (HCV)-RNA levels is integral to response-guided therapy. Rules for early discontinuation and determination of treatment duration were mainly established with HCV-RNA assays with a detection limit of 50IU/ml (COBAS Amplicor HCV [CA]). The currently used real-time PCR-based COBAS Ampliprep/COBAS-TaqMan HCV (CAP-CTM) test has a detection limit of approximately 10IU/ml. It is unknown whether shortening of treatment duration to 16/24 weeks in patients with rapid virological response at week 4 (RVR) and viral loads between 10 and 50IU/ml is possible. METHODS: We reanalysed stored serum from two large, multinational, randomized trials in which patients were treated with peginterferon alfa-2a/ribavirin (n=962). Results of CAP-CTM with truly undetectable HCV RNA and those <15IU/ml, which includes patients with residual viraemia (<15), were compared with the originally obtained results using the CA assay. RESULTS: RVR rates were comparable for CA (<50) and CAP-CTM (<15) with 32% and 32% for genotype (gt) 1 and 50% and 49% for gt2/3 patients, respectively. A significantly smaller number of samples really had truly undetectable HCV RNA by the CAP-CTM assay (24% for gt1, 37% for gt2/3). However, sustained virological response rates after shortened treatment (16/24weeks) were not significantly different in patients with a RVR <50, a RVR <15 and RVR undetectable (82%, 83%, 83% for 24weeks gt1 and 95%, 95%, 94% for 16weeks gt2/3). CONCLUSIONS: Shortening the treatment duration to 16/24weeks can be performed on the basis of a RVR with HCV-RNA concentrations <15IU/ml by the CAP-CTM assay.
Assuntos
Monitoramento de Medicamentos/métodos , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Ribavirina/uso terapêutico , Antivirais/uso terapêutico , Farmacorresistência Viral , Quimioterapia Combinada , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Valor Preditivo dos Testes , RNA Viral/genética , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes , Recidiva , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico , Viremia/virologiaRESUMO
BACKGROUND: Treatment with adefovir dipivoxil for 48 weeks resulted in histologic, virologic, and biochemical improvement in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We evaluated the effect of continued therapy as compared with cessation of therapy. METHODS: One hundred eighty-five HBeAg-negative patients with chronic hepatitis B were assigned to receive 10 mg of adefovir dipivoxil or placebo once daily for 48 weeks (ratio, 2:1). After week 48, patients receiving adefovir dipivoxil were again randomly assigned either to receive an additional 48 weeks of the drug or to switch to placebo. Patients originally assigned to placebo were switched to adefovir dipivoxil. Patients treated with adefovir dipivoxil during weeks 49 through 96 were subsequently offered continued therapy. The primary end points were changes in hepatitis B virus (HBV) DNA and alanine aminotransferase levels. RESULTS: Treatment with adefovir dipivoxil resulted in a median decrease in serum HBV DNA of 3.47 log copies per milliliter (on a base-10 scale) at 96 weeks and 3.63 log copies per milliliter at 144 weeks. HBV DNA levels were less than 1000 copies per milliliter in 71 percent of patients at week 96 and 79 percent at week 144. In the majority of patients who were switched from adefovir dipivoxil to placebo, the benefit of treatment was lost (median change in HBV DNA levels from baseline, -1.09 log copies per milliliter; only 8 percent of patients had levels below 1000 copies per milliliter at week 96). Side effects during weeks 49 through 144 were similar to those during the initial 48 weeks. Resistance mutations rtN236T and rtA181V were identified in 5.9 percent of patients after 144 weeks. CONCLUSIONS: In patients with HBeAg-negative chronic hepatitis B, the benefits achieved from 48 weeks of adefovir dipivoxil were lost when treatment was discontinued. In patients treated for 144 weeks, benefits were maintained, with infrequent emergence of viral resistance.
Assuntos
Adenina/análogos & derivados , Adenina/uso terapêutico , Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos/uso terapêutico , Adenina/administração & dosagem , Adenina/efeitos adversos , Adolescente , Adulto , Animais , Antivirais/administração & dosagem , Antivirais/efeitos adversos , DNA Viral/sangue , Método Duplo-Cego , Esquema de Medicação , Farmacorresistência Viral , Feminino , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Organofosfonatos/administração & dosagem , Organofosfonatos/efeitos adversos , Estudos Prospectivos , Fatores de TempoRESUMO
OBJECTIVE: Adherence to ribavirin is one factor that is critically important in the treatment of hepatitis C virus infection. However, ribavirin can be associated with clinically significant hemolytic anemia resulting in dose modifications in up to one-quarter of patients. Currently, baseline predictors of considerable anemia are not sufficiently discriminating for routine therapeutic intervention. The objective of this analysis was to elucidate baseline and on-treatment factors predictive of a considerable hemoglobin drop at week 4. METHODS: Multivariate logistic regression analysis was used to explore possible predictors for considerable hemoglobin decline (> or =2.5 g/dL) at week 4 among patients receiving peginterferon alfa-2a (40KD) and ribavirin (1,000/1,200 mg/day). RESULTS: A total of 555 patients were included in this analysis. At week 4, 236 patients exhibited a > or =2.5 g/dL decrease in hemoglobin. By regression analysis the most important independent variables associated with a decrease in hemoglobin of > or =2.5 g/dL were baseline creatinine clearance (P= 0.0003) and a rapid decline in hemoglobin of > or =1.5 g/dL at week 2 (P < 0.0001). Considerable hemoglobin decreases at week 4 were also significantly associated with early ribavirin dose reductions and a lower cumulative daily dose of ribavirin. CONCLUSION: Patients with impaired renal function may be at an increased risk of ribavirin-related anemia and should be monitored accordingly. Furthermore, a hemoglobin drop of > or =1.5 g/dL by week 2 was an excellent early predictor for subsequent considerable hemoglobin decreases and might be used to identify candidates for early intervention against anemia in order to help maintain ribavirin dosing and avoid suboptimal exposure.
Assuntos
Anemia/induzido quimicamente , Antivirais/administração & dosagem , Hepatite C/sangue , Hepatite C/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Adulto , Anemia/diagnóstico , Anemia/prevenção & controle , Antivirais/efeitos adversos , Feminino , Seguimentos , Hemoglobinas/metabolismo , Humanos , Interferon alfa-2 , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Proteínas Recombinantes , Ribavirina/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Currently, the approved dosage of ribavirin has not been studied in patients with 'normal' alanine aminotransferase (ALT) levels. METHODS: Modelling and simulations were performed using generalised additive models (GAMs) to predict the incidence of anaemia and rate of sustained virological response (SVR) in patients with hepatitis C virus (HCV) genotype 1 and persistently 'normal' ALT levels treated with peginterferon alpha-2a (40KD) 180 microg/week plus ribavirin 1000/1200 mg/day for 48 weeks. RESULTS: Model-based simulations predicted that SVR rates would increase from 39 to 48% if patients with genotype 1 and persistently 'normal' ALT levels had received the standard weight-adjusted dose of ribavirin. This was similar to the predicted 49% SVR rate for genotype 1 patients with elevated ALT levels. The incidence of anaemia was predicted to increase from 13% to 23% in patients with persistently 'normal' ALT activity and was higher than that predicted for patients with elevated ALT levels; however, the difference appeared to be largely explained by the higher proportion of women in the former group. CONCLUSIONS: Simulations based on GAM suggest that regimens for patients with HCV genotype 1 should include the standard weight-adjusted dose of ribavirin, as similar SVR rates are predicted to be achieved, regardless of patients' ALT status at baseline.
Assuntos
Alanina Transaminase/sangue , Anemia/etiologia , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/efeitos adversos , Simulação por Computador , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Hepatite C/genética , Humanos , Interferon alfa-2 , Masculino , Modelos Teóricos , Proteínas Recombinantes , Ribavirina/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVES: In primary biliary cirrhosis (PBC), the development of hepatocellular carcinoma (HCC) was thought to represent a rare complication. In contrast, extrahepatic malignancies have been reported to be significantly associated with PBC. The aim of this study was to determine the incidence of HCC and of extrahepatic malignancies in a large cohort of patients with PBC. METHODS: A total of 212 patients with documented PBC (19 men and 193 women) were followed up for a median of 6 (range, 1-23) years. RESULTS: In total, 23 (10.8%) cases of malignancy were diagnosed; eight (3.8%) patients with HCC and 15 (7.0%) with extrahepatic malignancies. PBC patients were found to have a 10-year risk of 4% for developing HCC and of 13% for developing extrahepatic malignancies. The risk for HCC was significantly higher in the PBC patients with cirrhosis (15% at 10 years of follow-up). In contrast, the histologic stage of PBC does not influence the risk for extrahepatic malignancy. CONCLUSION: Our study confirms that there is a risk of HCC in Greek patients with PBC, particularly in patients with stage IV PBC. The risk of extrahepatic malignancies is higher than that of HCC, but it is not influenced by the histologic stage of the liver disease.
Assuntos
Carcinoma Hepatocelular/etiologia , Cirrose Hepática Biliar/complicações , Neoplasias Hepáticas/etiologia , Adulto , Idoso , Neoplasias da Mama/etiologia , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Neoplasias dos Genitais Femininos/etiologia , Grécia/epidemiologia , Humanos , Incidência , Cirrose Hepática Biliar/epidemiologia , Cirrose Hepática Biliar/patologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Quantification of HBsAg in serum may be of clinical importance in predicting HBsAg seroconversion and complete response to treatment. METHODS: Serum HBsAg was quantified by ADVIA Centaur in 63 patients with HBeAg-negative chronic hepatitis B (CHBe-). A total of 42 had received interferon-alpha2b (IFN-alpha2b) (median 12.1 months; 19 sustained responders including 12 HBsAg-seroconvertors; 23 non-sustained responders) and 21 were on lamivudine (LAM) (median 33.0 months). Measurements were done at baseline, during and at the end of treatment, and during and at the end of follow-up. RESULTS: Baseline median [interquartile range (IQR)] HBsAg levels in all patients were 3286 (1602-7458) IU/ml, not different between IFN- and LAM-treated (P = 0.139). IFN significantly depressed HBsAg in all patients except IFN non-responders, but HBsAg decline persisted only in sustained responders. Low pretreatment HBsAg level was the only significant prognostic variable of HBsAg seroconversion by multivariate analysis. LAM treatment also suppressed HBsAg levels but at a significantly slower rate compared with IFN (P = 0.022). The median (IQR) estimated time to HBsAg undetectability (ETU-HBsAg), derived from best curve fitting, was 127 (87.6-263.5) months for LAM virological responders and 65.3 (36.3-95.0) months for IFN sustained responders (P = 0.002). In 12 HBsAg seroconvertors, ETU-HBsAg was similar to the real time of HBsAg loss (P = 0.525) and seroconversion (0.056). CONCLUSIONS: In CHBe-, IFN induces a sharper decrease in serum HBsAg compared with LAM and low pretreatment levels are significantly associated with HBsAg serocon-version. Serial HBsAg measurements may be useful for prediction of HBsAg loss and our data suggest that to achieve this, 5.4 years of sustained response to IFN or 10.6 years of effective LAM therapy are probably needed.
Assuntos
Antivirais/uso terapêutico , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Adulto , Alanina Transaminase/sangue , Antivirais/administração & dosagem , Estudos de Coortes , DNA Viral/sangue , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Feminino , Seguimentos , Vírus da Hepatite B/genética , Hepatite B Crônica/genética , Hepatite B Crônica/imunologia , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Proteínas Recombinantes , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: Adefovir dipivoxil, a nucleotide analogue, demonstrated clinically significant antiviral activity in patients with chronic hepatitis B in phase 1 and 2 clinical trials. METHODS: We randomly assigned 185 patients with chronic hepatitis B who were negative for hepatitis B e antigen (HBeAg) to receive either 10 mg of adefovir dipivoxil or placebo once daily for 48 weeks in a 2:1 ratio and a double-blind manner. The primary end point was histologic improvement. RESULTS: At week 48, 64 percent of patients who had base-line liver-biopsy specimens available in the adefovir dipivoxil group had improvement in histologic liver abnormalities (77 of 121), as compared with 33 percent of patients in the placebo group (19 of 57, P<0.001). Serum hepatitis B virus (HBV) DNA levels were reduced to fewer than 400 copies per milliliter in 51 percent of patients in the adefovir dipivoxil group (63 of 123) and in 0 percent of those in the placebo group (0 of 61, P<0.001). The median decrease in log-transformed HBV DNA levels was greater with adefovir dipivoxil treatment than with placebo (3.91 vs. 1.35 log copies per milliliter, P<0.001). Alanine aminotransferase levels had normalized at week 48 in 72 percent of patients receiving adefovir dipivoxil (84 of 116), as compared with 29 percent of those receiving placebo (17 of 59, P<0.001). No HBV polymerase mutations associated with resistance to adefovir were identified. The safety profile of adefovir dipivoxil was similar to that of placebo. CONCLUSIONS: In patients with HBeAg-negative chronic hepatitis B, 48 weeks of adefovir dipivoxil treatment resulted in significant histologic, virologic, and biochemical improvement, with an adverse-event profile similar to that of placebo. There was no evidence of the emergence of adefovir-resistant HBV polymerase mutations.
Assuntos
Adenina/análogos & derivados , Adenina/uso terapêutico , Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos , Adenina/efeitos adversos , Adolescente , Adulto , Idoso , Alanina Transaminase/sangue , Antivirais/efeitos adversos , Biópsia , DNA Viral/sangue , Método Duplo-Cego , Feminino , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Treatment with pegylated interferon (peginterferon) and ribavirin for 48 weeks is more effective than conventional interferon and ribavirin in patients with chronic hepatitis C. OBJECTIVE: To assess the efficacy and safety of 24 or 48 weeks of treatment with peginterferon-alpha2a plus a low or standard dose of ribavirin. DESIGN: Randomized, double-blind trial. SETTING: 99 international centers. PATIENTS: 1311 patients with chronic hepatitis C. INTERVENTION: Peginterferon-alpha2a, 180 microg/wk, for 24 or 48 weeks plus a low-dose (800 mg/d) or standard weight-based dose (1000 or 1200 mg/d) of ribavirin. MEASUREMENT: Sustained virologic response: undetectable HCV RNA concentration at the end of treatment and during 12 to 24 weeks of follow-up. RESULTS: Overall and in patients infected with HCV genotype 1, 48 weeks of treatment was statistically superior to 24 weeks and standard-dose ribavirin was statistically superior to low-dose ribavirin. In patients with HCV genotype 1, absolute differences in sustained virologic response rates between 48 and 24 weeks of treatment were 11.2% (95% CI, 3.6% to 18.9%) and 11.9% (CI, 4.7% to 18.9%), respectively, between standard- and low-dose ribavirin. Sustained virologic response rates for peginterferon-alpha2a and standard-dose ribavirin for 48 weeks were 63% (CI, 59% to 68%) overall and 52% (CI, 46% to 58%) in patients with HCV genotype 1. In patients with HCV genotypes 2 or 3, the sustained virologic response rates in the 4 treatment groups were not statistically significantly different. CONCLUSION: Treatment with peginterferon-alpha2a and ribavirin may be individualized by genotype. Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin; those with HCV genotypes 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks.
Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Adulto , Antivirais/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Masculino , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes , Ribavirina/efeitos adversosRESUMO
PURPOSE: We evaluated whether infection with Helicobacter pylori, including specific cytotoxic-associated antigen (CagA)-positive strains, increase the risk of upper gastrointestinal bleeding in users of nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: Cases with upper gastrointestinal bleeding and recent NSAID use, including aspirin, who were admitted during 2001, were compared with age- and sex-matched outpatient controls who had recent NSAID use. H. pylori infection was diagnosed by serum antibodies or the (13)C-urea breath test; and CagA seropositivity was diagnosed by enzyme-linked immunoassay. RESULTS: H. pylori was detected significantly more frequently in cases of bleeding than controls (79% [63/80] vs. 56% [45/80], P = 0.004). Cases of bleeding were more likely than controls to have a history of peptic ulcer (34% [n = 27] vs. 13% [n = 10], P = 0.003), previous upper gastrointestinal bleeding (19% [n = 15] vs. 6% [n = 5], P = 0.03), recent dyspepsia (29% [n = 23] vs. 15% [n = 12], P = 0.06), and <3 months of NSAID use (58% [n = 46] vs. 40% [n = 32], P = 0.04). CagA positivity was not associated with gastrointestinal bleeding. In a multivariate analysis, H. pylori infection was the only significant risk factor for upper gastrointestinal bleeding (odds ratio = 1.7; 95% confidence interval: 1.2 to 2.5; P = 0.004). CONCLUSION: H. pylori infection almost doubles the risk of upper gastrointestinal bleeding among users of NSAIDs.